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Paolo Vineis University of Torino and ISI Foundation, Torino, Italy e-mail address: [email protected] GENE-ENVIRONMENT INTERACTIONS IN CANCER LIMITATIONS OF GENETIC DETERMINISM 1. HUMANS AND MICE HAVE THE SAME ESTIMATED NUMBER OF EXPRESSED GENES 2. HUMANS AND CHIMPANZEES SHARE 98% OF THE GENOME 3. THE SEQUENCE INFORMATION IN DNA IS INSUFFICIENT TO DETERMINE HOW GENE PRODUCTS INTERACT TO PRODUCE AN ORGANISM 4. GENETIC PATHWAYS COMPLETELY SPECIFY ORGANISMAL FUNCTION ONLY IN RARE CASES, I.E. MONOGENIC DISEASES (SICKLE CELL ANEMIA, MUSCULAR DISTROPHY), WHEN THE CELL HAS NO COMPENSATORY MECHANISM AND ENVIRONMENTAL INFLUENCES ARE NIL – “ONE MUTANT GENE – ONE DISEASE PARADIGM” STROHMAN: “THE CELL IS STARTING TO LOOK MORE LIKE A COMPLETE ADAPTIVE SYSTEM RATHER THAN A FACTORY FLOOR OF ROBOTIC MACHINE GENES” SOME FIGURES LIFETIME RISK OF BREAST CANCER IS 12.6% IN WOMEN, OF PROSTATE CANCER IS 15.9% IN MEN, AND OF COLON CANCER IS 5.6% IN BOTH SEXES BRCA1 AND BRCA2 CONFER A RELATIVE RISK OF BREAST CANCER OF 5-10 GENOTYPES AT MISMATCH REPAIR LOCI CONFER A RR OF COLON CANCER OF 9.3 METABOLIC POLYMORPHISMS CONFER A RR FOR SEVERAL TYPES OF CANCER OF LESS THAN 2 ABOUT 0.25% OF WOMEN CARRY BRCA1 OR BRCA2 SUSCEPTIBLE VARIANTS, AND 0.1% OF PEOPLE HAVE SUSCEPTIBLE VARIANTS FOR MISMATCH REPAIR LOCI THESE GENOTYPES ACCOUNT FOR LESS THAN 5% OF BREAST OR COLON CANCERS 20% OF THE GENERAL POPULATION HAVE THE APOLIPOPROTEIN E4 ALLELE, WITH A RR OF ALZHEIMER’S DISEASE OF ABOUT 2; THIS GENE ACCOUNTS FOR 16.7% OF ALL CASES OF AD HOW MANY CANCERS ARE ATTRIBUTABLE TO GENETIC PREDISPOSITION? LICHENSTEIN ET AL, N ENGL J MED 343: 78-85, 2000 44,788 PAIRS OF TWINS STUDIED IN SCANDINAVIAN COUNTRIES ESTIMATES: PROSTATE 42% (95% CI 29-55) COLORECTAL 35% (10-48) BREAST 27% (4-54) EDITORIAL BY R. HOOVER: GENE-ENVIRONMENT INTERACTIONS ARE NOT ACCOUNTED FOR (THESE ARE PROBABLY OVERESTIMATES) ATTENTION TO DIFFERENT RISK MEASURES: ABSOLUTE RISK, E.G. LIFE-TIME CUMULATIVE RISK (50-70% OF BREAST CANCERS FROM BRCA1 MUTATIONS IN MUTATION CARRIERS) RELATIVE RISK (PENETRANCE)=5-10 TIMES ARe =PROPORTION AMONG CARRIERS= 80% OF BREAST CANCERS IN CARRIERS OF BRCA1 MUTATIONS ARE DUE TO THIS GENE ARp = PROPORTION IN THE POPULATION=5-10% OF ALL BREAST CANCERS ARE ATTRIBUTABLE TO BRCA1 MUTATIONS WHEN ESTIMATING THE EFFECTIVENESS OF “SCREENING” WE HAVE TO CONSIDER: (A) PREDICTIVE VALUE, THAT DEPENDS ON THE PREVALENCE OF MUTATIONS (B) PENETRANCE OF THE GENE (NNT) (C) MOST IMPORTANT, THE AVAILABILITY OF PREVENTIVE OR CURATIVE MEASURES EXAMPLE: MUTATION YES NO TEST POSITIVE 15 10 NEGATIVE 5 115 PREVALENCE=20/145=13.8% SENSITIVITY=15/20=0.75 SPECIFICITY=115/125=0.92 POSITIVE PREDICTIVE VALUE=15/25=0.60 I.E. OUT OF 100 POSITIVE TESTS 60 HAVE THE MUTATION EXAMPLE: MUTATION YES NO TEST POSITIVE 15 1000 NEGATIVE 5 11500 PREVALENCE=20/12520=0.16% SENSITIVITY=15/20=0.75 SPECIFICITY=11500/12500=0.92 POSITIVE PREDICTIVE VALUE=15/1015=0.015 I.E. OUT OF 1015 POSITIVE TESTS ONLY 15 HAVE THE MUTATION WHAT IS THE EFFECT OF PENETRANCE? IMAGINE WE HAVE AN EFFECTIVE PREVENTIVE MEASURE THAT REDUCES THE RISK OF DISEASE IN THE SCREENEES BY 58% LET US IMAGINE THAT THE RISK OF DISEASE IS 1.4% FOR A LOW PENETRANT MUTATION AND 37% FOR A HIGHLY PENETRANT MUTATION (REALISTIC FIGURES FOR A METABOLIC POLYMORPHISM AND BRCA1, RESPECTIVELY) WE COMPUTE THE NUMBER NEEDED TO TREAT (SCREEN), I.E. THE NUMBER OF MUTATIONS CARRIERS WHO NEED TO UNDERGO SCREENING TO PREVENT A SINGLE CANCER THE NNT(S) DEPENDS ON PENETRANCE PLUS THE EFFECTIVENESS OF PREVENTIVE MEASURES WITH 58% SUCCESSES AND A RISK OF DISEASE OF 37%, THE NUMBER OF CASES DECREASES BY 22%. THE RECIPROCAL OF 0.22 IS APPROXIMATELY 4.5 WITH A RISK OF DISEASE OF 1.4% AND 58% SUCCESSES, THE RISK DECREASES BY 0.008 AND ITS RECIPROCAL IS 1/0.008=125 I.E. WE NEED TO TREAT 4.5 SUBJECTS IN THE FIRST CASE AND 125 IN THE SECOND (NNT) NOW WE CAN COMBINE THE NNT AND PREVALENCE TO OBTAIN THE NNS CASE 1 IF WE SCREEN THE GENERAL POPULATION FOR A LOW PENETRANT GENE (NNT=125, PREVALENCE=13.8%, PPV=60%), IN ORDER TO PREVENT A CANCER WE HAVE TO MULTIPLY THE NNT BY THE RECIPROCAL OF PREVALENCE 125 X (1/0.138) = 906 SUBJECTS (WITHOUT CONSIDERING SENSITIVITY AND SPECIFICITY) CASE 2 IF WE SCREEN THE GENERAL POPULATION FOR A RARE, HIGHLY PENETRANT GENE (NNT=4.5, PREVALENCE=0.16%, PPV=1.5%), IN ORDER TO PREVENT A CANCER WE HAVE TO MULTIPLY THE NNT BY THE RECIPROCAL OF PREVALENCE 4.5 X (1/0.0016) = 2813 SUBJECTS (WITHOUT CONSIDERING SENSITIVITY AND SPECIFICITY) CASE 3 IF WE SCREEN FAMILIES FOR A RARE, HIGHLY PENETRANT GENE (NNT=4.5, PREVALENCE IN THE FAMILIES=0.50), IN ORDER TO PREVENT A CANCER WE HAVE TO MULTIPLY THE NNT BY THE RECIPROCAL OF PREVALENCE 4.5 X (1/0.50) = 90 SUBJECTS (WITHOUT CONSIDERING SENSITIVITY AND SPECIFICITY) Calculation of the Number Needed to Screen in the case of screening for a low penetrant gene (GSTM1 in smokers), and a highly penetrant gene (BRCA1), respectively in the general population or in families (from Vineis et al, The Lancet, 357: 709-712, 2001) Lung cancer in workers exposed to PAH GSTM1 null GSTM1 wild 1.34 (1.21 - 1.48) (a) 1.0 Cumulative risk 13% Risk reduction Breast cancer BRCA1 BRCA1 general population families 5 10 10% 40% (b) 80 % 50% 50% (c) 50% (Tamoxifen or Raloxifene) (d) 50% Cumulative risk after intervention 6.5% 5% 20% 40% Absolute risk reduction 6.5% 5% 20% 40% Relative risk Lung cancer Breast cancer GSTM1 null GSTM1 wild BRCA1 general population NNS in mutation carriers 15 20 5 2.5 Prevalence 50% 50% 0.2% (e) 50% 40 2,500 NNS in whole target population 30 NNS in all occupationally exposed BRCA1 families 5 35 (a) from Vineis et al, IARC Scie. Publ. No. 148, 1999 1999 (b) from Hopper et al, 1999 (c) theoretical maximum reduction in risk of lung cancer due to preventive action (d) theoretical benefit, based on the BCPT trial with a 45% benefit, and the Raloxifene trial with a 76% benefit (e) Coughlin et al, 1999 An illustration of the principle of “one exposure - many diseases, one disease - many low penetrant genes”. Exposure Proportion attributable Tobacco smoke Lung cancer Bladder cancer Occupational exposure to PAH Lung cancer Bladder cancer (a) depending on the areas 90% 70% men 30% women Larynx cancer 90% CHD 12.5% Chronic bronchitis 80% 4-20% (a) 1-10% (a) Disease Low penetrant genes Odds Ratio (a) Lung cancer CYP1A1 MspI (asians) CYP1A1 MspI (caucasians) CYP1A1 Exon 7 (asians) CYP1A1 Exon 7 (caucasians) CYP2D6 GSTM1 1.73 1.04 2.25 1.30 1.26 1.34 Bladder cancer NAT - 2 slow GSTM1 1.37 1.57 Colon cancer NAT - 2 rapid 1.19 (a) meta - analisys from Vineis et al, IARC Scie. Publ. No. 148, 1999 MANY GENES CONTRIBUTE TO MODULATE THE RISK, AND THE CONTRIBUTION OF EACH IS MODEST ( EXCEPT IN HIGH RISK FAMILIES) ADOPTING PREVENTIVE MEASURES ONLY IN THE HIGHLY SUSCEPTIBLE WOULD IMPLY VERY LITTLE ADVANTAGES OVER PREVENTION FOR ALL